This invention relates to a novel process of diastereoselective hydrogenation of 1,3-hydroxyketones.
Stereoselective preparation of the 1,3-diol function has great utility in organic chemistry due to the occurrence of such a group in natural products. Besides enzymatic routes, there are also transition-metal-catalysed hydrogenation reactions described. For example, in Eur. J. Org. Chem. 1999, 1787-1793, the enantioselective homogeneous catalysis using rhodium- or ruthenium-bisphosphane complexes are described. However, the different proposed routes are not fully satisfactory.
It is therefore an object of the instant invention to provide for a hydrogenation process using a simple, commercially available heterogeneous catalyst which can be filtered off after the reaction. It is a further object that the process has a good selectivity and that the hydrogenation proceeds fast. It is also an object to provide for a process not using expensive compounds. A further object is a process which does not necessarily require low temperature thus avoiding cooling equipment. An even further object is a process whereby the waste problems are minimised.
Surprisingly, it has now been found that the addition of magnesium salts to a heterogeneous catalytic system based on platinum catalysts significantlyimproves the diastereoselective hydrogenation of 1,3-hydroxyketones. A further surprising improvement, especially with regard to the overall conversion and the diastereomeric ratio is observed when a catalytic amount of an oxidant such as H2O2 is added to the reaction mixture.
In general, the beneficial effects of the inventive reaction are observed for a large structural variety of 1,3-hydroxyketones and in general at least an increase in the conversion is observed by the addition of a magnesium salt and the optional addition of a catalytic amount of an oxidant. Such increase is in particular also observed for acyl derivatives of 1,3-hydroxyketones and 1,3-hydroxyketones which are twice substituted in the 2-position.
The invention especially relates to a process, wherein a compound of formula (I) 
wherein R, Rxe2x80x2 and Rxe2x80x3 are independently of each other a radical being compatible with the reaction conditions,
except compounds wherein
a) one R is H and the other R is xe2x80x94CH2CN, Rxe2x80x3 is H and Rxe2x80x2 is xe2x80x94C(xe2x95x90O)ORb and Rb is a H or a carboxy-protecting group;
b) one R is H and the other R is xe2x80x94CH2C(xe2x95x90O)NR*R**, Rxe2x80x3 is H and Rxe2x80x2 is xe2x80x94C(xe2x95x90O)ORb and R* and R** are independently of each other H or an amide-protecting group and Rb is H or a carboxy-protecting group;
c) one R is H and the other R is xe2x80x94CH2C(xe2x95x90O)ORb, Rxe2x80x3 is H and Rxe2x80x2 is xe2x80x94CH2xe2x80x94N3 and Rb is H or a carboxy-protecting group; and
d) one R is H and the other R is xe2x80x94CH2C(xe2x95x90O)ORb, Rxe2x80x3 is H and Rxe2x80x2 is xe2x80x94CH2xe2x80x94Rd and Rb is H or a carboxy-protecting group and Rd is halogen;
is reduced with hydrogen to the corresponding diol, which is predominantly in the form of the syn-diol, in the presence of a magnesium salt and a heterogeneous platinum catalyst in a solvent.
Unless otherwise indicated, halogen is preferably fluorine, chlorine, bromine or iodine.
Suitable compatible radicals R, whereby the two radicals R must be different from each other, are for example H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, xe2x80x94CH2CO2R4, xe2x80x94CHR4CO2R5, xe2x80x94CO2R4, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)NHR4, xe2x80x94CH2C(O)NR4R5, xe2x80x94CHR4C(O)NH2, xe2x80x94CHR4C(O)NHR5, xe2x80x94CHR4C(O)NR5R6, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHR4 and xe2x80x94C(O)xe2x80x94NR4R5, wherein R4, R5 and R6 are independently from each other alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl; to the extent possible said radicals may be branched or unbranched and may be unsubstituted or substituted. Preferred radicals R are H, alkyl (most preferred C1-C12-alkyl), aryl (most preferred phenyl or naphthyl), xe2x80x94CH2CO2R4, xe2x80x94CHR4CO2R5, xe2x80x94CO2R4, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)NHR4, xe2x80x94CH2C(O)NR4R5, xe2x80x94CHR4C(O)NH2, xe2x80x94CHR4C(O)NHR5, xe2x80x94CHR4C(O)NR5R6, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHR and xe2x80x94C(O)xe2x80x94NR4R5 which independently of each other may be unsubstituted or substituted. Also preferred are compounds where at least one radical R is H or lower alkyl, whereby H is particularly preferred. Suitable substituents are apparent from the given lists of compatible radicals and protecting groups. Preferred substituents are halogen, oxygen, nitrogen, hydroxy and lower alkoxy.
Suitable compatible radicals Rxe2x80x2 or Rxe2x80x3 are for example H, alkyl, alkoxy, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkyl-alkyl, cycloalkylalkoxy, aryl, aryloxy, aralkyl, aralkoxy, halogen, xe2x80x94OH, xe2x80x94OR4, xe2x80x94OC(O)R4, xe2x80x94NHxe2x80x94C(O)xe2x80x94R4, xe2x80x94NR4xe2x80x94C(O)xe2x80x94R4, xe2x80x94CO2R4, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHR4, and xe2x80x94C(O)xe2x80x94NR4R5, wherein R4 and R5 are independently from each other alkyl, cycloalkyl, cycloalkylalkyl, phenyl or benzyl; to the extent possible said radicals may be branched or unbranched and may be unsubstituted or substituted. Preferred radicals Rxe2x80x2 are H, alkyl (most preferred C1-C12-alkyl), aryl (most preferred phenyl or naphthyl), xe2x80x94CO2R4, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHR4, and xe2x80x94C(O)xe2x80x94NR4R5 which may be unsubstituted or substituted. Preferred radicals Rxe2x80x3 are H, alkyl (most preferred C1-C12-alkyl), cycloalkyl and aryl (most preferred phenyl or naphthyl) which independently of each other may be unsubstituted or substituted. Suitable substituents are apparent from the given lists of compatible radicals and protecting groups. Preferred substituents are halogen, oxygen, nitrogen, hydroxy and lower alkoxy.
The prefix xe2x80x9clower-xe2x80x9d or xe2x80x9clowerxe2x80x9d indicates that the radical in question contains preferably up to 7 carbon atoms, especially up to 4 carbon atoms. Lower alkyl is therefore preferably C1-C7-alkyl, especially C1-C4-alkyl, and may be unbranched or branched one or more times, insofar as possible. Cyclic radicals, such as cycloalkyl, have at least 3 carbon atoms, especially from 3 to 7.
Carboxy-protecting groups are especially ester-forming, enzymatically and/or chemically removable protecting groups, preferably enzymatically and/or chemically removable protecting groups, such as heptyl, 2-N-(morpholino)ethyl, cholinyl, methoxyethoxyethyl or methoxyethyl; or those which are primarily chemically removable, e.g. alkyl, such as lower alkyl, especially methyl, ethyl, substituted lower alkyl (except for benzyl and substituted benzyl), such as substituted methyl, especially 9-fluorenylmethyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, 2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, pivaloyloxymethyl, phenylacetoxymethyl, triisopropylsilylmethyl, 1-3-dithianyl-2-methyl, dicyclopropylmethyl, acetonyl, phenacyl, p-bromophenacyl, xcex1-methylphenacyl, p-methoxyphenacyl, desyl, carbamidomethyl, p-azobenzenecarboxamidomethyl, N-phthalimidomethyl or 4-picolyl, 2-substituted ethyl, especially 2-iodo-, 2-bromo- or 2-chloro-ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-methylthioethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2xe2x80x2-pyridyl)ethyl, 2-(p-methoxyphenyl)ethyl, 2-(diphenylphosphino)ethyl, 1-methyl-1-phenylethyl, 2-(4-acetyl-2-nitrophenyl)ethyl or 2-cyanoethyl, tert-butyl, 3-methyl-3-pentyl, 2,4-dimentyl-3-pentyl or xcfx89-chloro-lower alkyl, especially 4-chlorobutyl or 5-choropentyl, cyclopentyl, cyclohexyl, lower alkenyl, especially allyl, methallyl, 2-methylbut-3-en-2-yl, 3-methylbut-2-enyl or 3-buten-1-yl, substituted lower alkenyl, especially 4-(trimethylsilyl)-2-buten-1-yl, cinnamyl or xcex1-methylcinnamyl, lower alkynyl, such as prop-2-ynyl, phenyl, substituted phenyl, especially 2,6-dialkylphenyl, such as 2,6-dimethylphenyl, 2,6-diisoproylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 2,6-di-tert-butyl-4-methoxyphenyl, p-(methylthio)phenyl or pentafluorophenyl, benzyl, substituted benzyl, especially triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzosuberyl, 1-pyrenylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl, 2,4,6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2-6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, 4-azidomethoxybenzyl, 4-{N-[4,4-dimethyl,2,6-dioxocyclohexylidene)-3-methylbutyl]amino}benzyl, piperonyl or p-polymer-benzyl, tetrahydropyranol, tetrahydrofuranyl, or silyl radicals, such as tri-lower alkylsilyl, especially trimethylsilyl, triethylsilyl, tert-butyldiemethylsilyl, isopropyldimethylsilyl or di-tert-butylmethylsilyl, or phenyl-di-lower alkylsilyl, such as phenyldimethylsilyl; alternatively a carboxy group can also be protected in the form of an oxazolyl, 2-alkyl-1,3-oxazolinyl, 4-alkyl-5-oxo-1,3-oxazolodinyl or 2,2-bistrifluoromethyl-4-alkyl-5-oxo-1,3-oxazolodinyl radical.
Amide-protecting groups are especially allyl, tert-butyl, N-methoxy, N-benzoyloxy, N-methylthio, triphenylmethylthio, tert-butyldimethylsilyl, triisopropylsilyl, 4-(methoxymethoxy)phenyl, 2-methoxy-1-naphthyl, 9-fluorenyl, tert-butoxycarbonyl, N-benzyloxycarbonyl, N-methoxy- or N-ethoxy-carbonyl, toluenesulfonyl, N-buten-1-yl, 2-methoxycarbonylvinyl, or especially alkyl, such as lower alkyl, or more especially substituted alkyl, especially benzyl, benzyl substituted by one ore more radicals selected from lower alkoxy, such as methoxy, lower alkanoyloxy, such as acetoxy, lower alkylsulfinyl, such as methylsulfinyl, dicyclopropylmethyl, methoxymethyl, methylthiomethyl and N-benzoyloxymethyl; or bis(trimethylsilyl)methyl, trichloroethoxymethyl, tert-butyldimethylsilyloxymethyl, pivaloyloxymethyl, cyanomethyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl, o-nitrobenzyl, bis(4-methoxyphenyl)phenylmethyl, bis(4-methylsulfinylphenyl)methyl, pyrrolidinomethyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl or 2-(4-methylsulfonyl)ethyl.
It is a characteristic of protecting groups that they are simple to remove (that is to say without undesirable secondary reactions taking place), for example by solvolysis, reduction, photolysis or alternatively under conditions analogous to physiological conditions, for example enzymatically.
The instant hydrogenation process yields predominantly syn-diols. Depending on the substrate (compound of formula (I)) and the process conditions the syn-diol exceeds, for example, 60%, preferably 70% and most preferred 90%, of the total diol produced.
Suitable solvents are alcohols, especially lower alkanoles such as methanol, ethanol, propanol or butanol, or ethylenglykol, diethylenglykol, ethylenglykolmonomethyl- or monoethylether, diethylenglykolmonomethyl- or monoethyletheror ketones such as acetone or methylisobutylketone. The solvent may also be a mixture of solvents or a mixture of a solvent or solvents with water, for example a mixture of methanol with water.
A suitable ratio by weight of such a catalyst in relation to the substrate is between 1:5 and 1:100, preferably between 1:7 and 1:15.
Heterogeneous platinum catalysts are known per se, are well described in the literature and are commercially available. It is possible to use platinum in the form of the pure metal, for example as a powder, or, what is preferred, in the form of finely distributed metal on a support. A suitable support material is for example carbon, metal oxides like SiO2, TiO2, Al2O3, metal salts, and natural or synthetic silicates. The catalyst may also be in the form of colloidal platinum. The amount of platinum metal is for example 1 to 10% by weight, preferably 3 to 8% by weight, relative to the support.
The hydrogenation is carried out for example with a hydrogen pressure of up to 200 bar, preferably with a hydrogen pressure of 1 to 200 bar and most preferred with a hydrogen pressure of 5 to 40 bar.
The reaction is carried out, for example, at a temperature between 0 and 80xc2x0 C., especially between 20 to 25xc2x0 C.
Suitable magnesium salts are the customary salts in hydrated or pure form, for example magnesium acetate, magnesium chloride, magnesium bromide, magnesium ascorbate, magnesium gluconate, magnesium stearate, magnesium nitrate, magnesium sulfate and magnesium citrate whereby magnesium acetate (especially as the tetrahydrate) is particularly preferred.
A suitable ratio by weight of the magnesium salt to the heterogeneous platinum catalyst in the instant process is from 10:1 to 1:10, preferably from 5:1 to 1:5, and most preferred from 5:1 to 1:2, whereby for above calculation purpose the magnesium salt is in the form of magnesium acetate and the heterogeneous catalyst is in the form of a carbon support with 5% by weight of platinum.
A further aspect of the instant invention is the process, wherein a compound of formula (I) 
wherein R, Rxe2x80x2 and Rxe2x80x3 are independently of each other a radical being compatible with the reaction conditions,
is reduced with hydrogen to the corresponding diol, which is predominantly in the form of the syn-diol, in the presence of a magnesium salt and a heterogeneous platinum catalyst in a solvent, whereby a catalytic amount of an oxidant is added to the reaction mixture. The definitions, preferences and reaction conditions given above are also valid for this aspect of the invention.
Suitable oxidants are, for example, ozone, organic or inorganic peroxides and preferably air, oxygen or H2O2 (most preferred 30% H2O2 in water), whereby the oxidant is added to a suspension of substrate and catalyst prior to pressurizing with hydrogen. Preferably such catalytic amount is 1 to 100 xcexcl H2O2 per 100 mg of substrate used (or the respective molar equivalent in case of a different oxidant).
Compounds of formula (I) are preferred wherein one radical R is H, Rxe2x80x3 is H and R or Rxe2x80x2 is xe2x80x94C(xe2x95x90O)ORb and Rb is H or a carboxy-protecting group.
Compounds of formula (I) are preferred wherein one radical R is H, Rxe2x80x3 is H and R is xe2x80x94C(xe2x95x90O)ORb; Rxe2x80x2 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl and Rb is H or a carboxy-protecting group.
Compounds of formula (I) are preferred wherein one radical R is H or lower alkyl and the other radical R is H, alkyl or aryl, Rxe2x80x2 is xe2x80x94CO2R4, xe2x80x94C(O)NH2, xe2x80x94C(O)NHR4 or xe2x80x94C(O)NR4R5, R4 and R5 areindependently from each other alkyl and Rxe2x80x3 is H, C1-C12-alkyl), cycloalkyl or aryl.
Compounds of formula (I) are preferred wherein one radical R is H or lower alkyl and the other radical R is xe2x80x94CH2CO2R4, xe2x80x94CHR4CO2R5, xe2x80x94CO2R4, xe2x80x94CH2C(O)NH2, xe2x80x94CH2C(O)NHR4, xe2x80x94CH2C(O)NR4R5, xe2x80x94CHR4C(O)NH2, xe2x80x94CHR4C(O)NHR5, xe2x80x94CHR4C(O)NR5R6, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(O)xe2x80x94NHR4 or xe2x80x94C(O)xe2x80x94NR4R5;
Rxe2x80x2 is substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
R4, R5 and R6 are independently from each other alkyl and
Rxe2x80x3 is H, C1-C12-alkyl, cycloalkyl or aryl.